Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that displays highly heterogeneous clinical and biological manifestations. It is characterized by an excessive production of type I interferon (IFN) and proinflammatory cytokines, breakdown of tolerance to self-nucleic acids, and development and deposition of immune complexes in multiple organs. Beyond these hallmarks, metabolic abnormalities, such in glycolysis and mTOR signaling, in different types of immune cells, such as T cells, macrophages, dendritic cells (DCs) and neutrophils have been reported. Despite these pathological events, SLE remains an incurable disease highlighting the clinical unmet need for improved molecular biomarkers for patient treatment stratifications and advances in developmental therapeutics to combat the disease process. Cells secrete a wide variety of soluble factors and extracellular particles to mediated intercellular communication under both physiological and pathological conditions. Emerging evidence suggests that secreted factors influence specific functions in autoimmune diseases. By employing the state-of-art asymmetric-flow field-flow fractionation (AF4) technology, we have identified a novel population of non- membranous nanoparticles termed ?exomeres? (~35 nm), which is indeed the predominant nanoparticles secreted by most cells, including peripheral blood mononuclear cells from SLE patients (preliminary data). Exomeres demonstrate biophysical properties different from other extracellular vesicles, and contain unique molecular contents, representing potential source of self-antigens and clinical biomarkers. Importantly, proteomic analysis of tumor cell-derived exomeres revealed an enrichment of metabolic enzymes, especially in glycolysis and mTOR signaling. Our preliminary study has shown that uptake of tumor-derived exomeres by Kupffer cells (resident macrophages in liver) resulted in metabolic alterations in the liver. Therefore, we hypothesize that circulating exomeres function as pathologic mediators in SLE development and reprogram the metabolism in target cells. To test this hypothesis, we will employ our expertise in the AF4 technology to identify and characterize exomeres present in the plasma (Aim 1.1) and secreted by circulating immune cells (B cells and monocytes) (Aim 1.2) from SLE patients and healthy control subjects. Biophysical properties and molecular composition (proteins, metabolites and nucleic acids) of these particles will be characterized. We will investigate the functional roles of exomeres in SLE pathogenesis by examining their impact upon immune cell activation, IFN production, oxidized mitochondrial DNA extrusion from neutrophils, and plasmacytoid DC activation (Aim 2.1). Specifically, we will examine whether exomeres from the plasma of SLE patients alternate the metabolic processes in their target cells (Aim 2.2). This study will provide a novel resource of biomarkers for SLE patient stratification and disease activity evaluation. Furthermore, understanding how circulating exomeres function will guide the design of successful therapeutic strategies.